Substance P receptor blockage has dramatic protective effects against the cardiovascular pathology observed in animals placed on a severe Mg- deficient diet (MgD9 or 9% of RDA for Mg), implicating neurogenic hyper activation as a key event associated with this pathology. Our data suggest that elevated substance P induces production of nitric oxide (NO.) and other active oxygen species which may heighten the sensitivity of MgD9 animals to ischemia/reperfusion (I/R stress. This proposal will determine the minimal dietary threshold level of Mg which continues to elicit similar neurogenic hyperactivity observed with MgD9 diet. Specifically, moderate (40% RDA) and marginal (60-85%) dietary MgD rat models will be used to examine five specific aims: 1) Establish the detection time-courses of circulating and tissue neurogenic events during prolonged Mg deficiency, and the minimal threshold of level of dietary Mg restriction which still causes the cardiovascular pathobiology observed in severe Mg-deficiency; 2) Determine if susceptibility to I/R stress is enhanced by moderate and marginal Mg restricted diets, and the contribution of elevated neuropeptides and N0. synthesis in the injury process; 3) Investigate whether endogenous NMDA receptor activation mediates release of neuropeptides during moderate and marginal MgD, and if this is a calcium-triggered mechanism; 4) Determine if Mg- restriction induces cellular up-regulation of neuropeptide receptors; and 5) Determine if the neurogenic response associated with MgD is a consequence of new synthesis of substance P from neuronal and non- neuronal sources. We hypothesize that less severe MgD diets can induce hyper activation of NMDA receptors causing excessive release of neuronal mediators which enhance cell production of superoxide and NO. in vivo, and reduce the tolerance of animal tissues to applied I/R stress. These studies will provide insight concerning the role of neurogenic inflammation in the cardiovascular pathologic consequences of clinically- achievable Mg-deficiency.